Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting.

Sulfasalazine is characterized by low intestinal absorption, which essentially enables its colonic targeting and therapeutic action. The mechanisms behind this low absorption have not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of sulfasalazine as a potential mechanism for its low small-intestinal absorption and colonic targeting following oral administration.

An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in Complex Regional Pain Syndrome type 1 patients.

Aims: The aim of the study was to explore the analgesic effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients.

Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied.

Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.

Background: Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice.

Methods: Nociception after acute injection (10 mg/kg) and chronic infusion (1.

Nicotine modulates bone metabolism-associated gene expression in osteoblast cells.

Smoking has a broad range of physiological effects, such as being a risk factor in osteoporosis, bone fracture incidence, and increased nonunion rates. Recent studies showed that nicotine has effects at the cellular level in human osteoblast cells. To identify possible mechanisms underlying nicotine-induced changes in osteogenic metabolism, we defined changes in proliferation and osteocalcin, type I collagen, and alkaline phosphatase gene expression after treating human osteosarcoma cells (MG63), with various concentration of nicotine.

A proposed role for the psychiatrist in the treatment of adolescents with type I diabetes.

Type I diabetes is a chronic illness that most frequently develops during childhood. As a medical doctor with an understanding of psychology and human development, the psychiatrist is in a unique position to guide the child or adolescent with diabetes and his family through the typical lifestyle adjustments that are encountered when diagnosed with diabetes. This article presents an overview of the diagnosis and management of type I diabetes, reviews the ways in which diabetes will interact with child development, and discusses the increased rates of eating disorders and mood disorders among children with type I diabetes.

Mixed-effects modeling of the influence of midazolam on propofol pharmacokinetics.

Background: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol.

The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport.

The aim of this study was to elucidate the intestinal epithelial cell efflux transport processes that are involved in the intestinal transport of the H(2) receptor antagonist nizatidine. The intestinal epithelial efflux transport mechanisms of nizatidine were investigated and characterized across Caco-2 cell monolayers, in the concentration range 0.05-10 mM in both apical-basolateral (AP-BL) and BL-AP directions, and the transport constants of P-glycoprotein (P-gp) efflux activity were calculated.

Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.

The aim of this research was to gain a mechanistic understanding of ion-pair mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass transport analyses were developed to describe the ion-pair mediated octanol-buffer partitioning and hydrophobic membrane permeation of the model basic drug phenformin. Three lipophilic counterions were employed: p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic acid (HNAP).

Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs.

The purpose of this study was to investigate the role of P-gp efflux in the in vivo intestinal absorption process of BCS class III P-gp substrates, i.e. high-solubility low-permeability drugs.

Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein.

Purpose: To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate.

Methods: Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined.

A comparative study of two methods for attaining constant alcohol levels.

Aims: Alcohol effects or drug-alcohol interactions are preferably studied at constant blood levels. To achieve pseudo-steady state levels, various methods are used, which usually produce adequate averages but variable individual concentration profiles. The aim was to compare two modes of alcohol administration: a 'two-step prekinetic procedure' and a 'clamping method'.

Segmental-dependent membrane permeability along the intestine following oral drug administration: Evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat.

In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine.

Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect.

Background: It would be useful to have an open-source electroencephalographic (EEG) index of gamma-amino-butyric acid (GABA)-ergic anaesthetic drug effect that is resistant to eye-blink artifact, responds rapidly to changes in EEG pattern, and can be linked to underlying neurophysiological and neuropharmacological mechanisms that control the conscious state.

Methods: The EEG waveform can be described as a sequence of ordinal patterns. The permutation entropy (PE) describes the relative occurrence of each of these patterns.

Differential effect of morphine and morphine-6-glucuronide on the control of breathing in the anesthetized cat.

Background: Morphine's metabolite, morphine-6-glucuronide (M6G), activates the mu-opioid receptor. Previous data suggest that M6G activates a unique M6G receptor that is selectively antagonized by 3-methoxynaltrexome (3mNTX). The authors compared the effects of M6G and morphine on breathing in the anesthetized cat and assessed whether 3mNTX reversal was selective for M6G.

Population pharmacokinetic-pharmacodynamic modeling of epidural anesthesia.

Background: In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e.

Sex-specific responses to opiates: animal and human studies.

It is widely reported that analgesic drugs acting at mu, kappa, and delta opioid-receptors display quantitative and qualitative differences in effect in males and females. These sex-related differences are not restricted to the analgesic/antinociceptive properties of opioids, but are also present in opioid-induced side effects, such as changes in respiration, locomotor activity, learning/memory, addiction, and changes in the cardiovascular system. An increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids show that, although sex may affect opioid analgesia, the direction and magnitude of sex differences depend on many interacting variables.

Efficacy and safety of morphine-6-glucuronide (M6G) for postoperative pain relief: a randomized, double-blind study.

Aims: The aim of the study was to assess analgesia and safety effects of a range of intravenous doses of M6G (10, 20 and 30 mg/70 kg), compared to placebo, in postoperative patients.

Methods: In a randomized, multicentre, double-blind study, patients undergoing knee replacement surgery under spinal anaesthesia were administered one of three doses of M6G, or placebo, 150 min after spinal nerve block. Morphine rescue medication was available via a PCA pump.

Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.).

Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system.

Analysis of cerebrospinal fluid inflammatory mediators in chronic complex regional pain syndrome related dystonia.

Objectives: There is compelling evidence of central nervous system involvement in neuropathic pain and movement disorders in patients with complex regional pain syndrome (CRPS). Previously, elevated cerebrospinal fluid (CSF) levels of interleukin-1beta and interleukin-6 were found in CRPS patients with and without movement disorders. The aim of the present study was to replicate these findings and to search for additional CSF biomarkers in chronic CRPS patients with dystonia.

Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine.

Buprenorphine is relatively resistant to reversal by naloxone. We tested the effect of various doses and infusion schemes of naloxone on buprenorphine-induced respiratory depression and compared the data with naloxone-reversal of morphine and alfentanil-induced respiratory depression. Both morphine and alfentanil were easily reversed by low doses of naloxone (0.

Plasticity in the brain: influence of bilateral carotid body resection (bCBR) on central CO2 sensitivity.

We investigated the effect of bilateral carotid body resection (bCBR) in a patient with bilateral carotid body tumors on central CO2 sensitivity. We applied multiple square-wave changes in end-tidal CO2 and measured ventilation before the first surgery and at regular intervals for 3 years after surgery. The data were analyzed using a two-compartment model of the ventilatory control system.

The oral absorption of phospholipid prodrugs: in vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration.

The purpose of this study was to evaluate the oral absorption characteristics of a phospholipid-drug conjugate, comprising direct conjugation between the lecithin and the drug moiety through the sn-2 position. We investigated the mechanisms involved with the trafficking of this conjugate following oral administration in the gastrointestinal (GI) lumen, within the enterocyte and further. A phospholipid-valproic acid conjugate (DP-VPA) was utilized as a model molecule.

Postoperative epidural analgesia after total knee arthroplasty with sufentanil 1 microg/ml combined with ropivacaine 0.2%, ropivacaine 0.125%, or levobupivacaine 0.125%: a randomized, double-blind comparison.

Background And Objectives: Total knee replacement is associated with severe postoperative pain that, if treated insufficiently, interferes with early rehabilitation. The purpose of the present study is to compare the efficacy of ropivacaine (0.2% and 0.